Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034063 (pulmonary edema)
 10,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary thiomides such as thiobenzamide (TB) are well known hepatotoxins in the rat. Among para-substituted TB derivatives relative hepatotoxicity varies in accordance with the electronic properties of the parasubstituent. In contrast, several N-substituted TBs have been found to be potent lung toxins in rats and mice. For N-methylthiobenzamide (NMTB) the LD50 was found to be 0.315 (95% confidence interval (CI) 0.228-0.436) mmol/kg in the rat and 0.224 (95% CI 0.191--0.264) mmol/kg in the mouse. The N-mono-substituted TBs produce alveolar and perivascular pulmonary edema, together with massive pleural effusions (hydrothorax). In this regard their toxicity resembles qualitatively that of the arylthioureas. Furthermore, pretreatment of rats with sub-lethal doses of NMTB was found to protect them against subsequent challenge with supra-lethal doses. N,N-Dimethylthiobenzamide (DMTB) also causes lung injury in the rat, but only at much higher doses than with the N-mono-substituted TBs. The similarity in toxic responses elicited by the N-mono-substituted TBs and the arylthioureas is paralleled by similarities in their chemical structures and their metabolic disposition which involves (among other things) S-oxygenation by the microsomal flavin-containing monooxygenase (EC 1.14.13.8). Thus, a possible role for S-oxidized metabolites in the lung toxicity of these compounds must be considered.
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PMID:Pneumotoxic effects of thiobenzamide derivatives. 708 87

Thiourea-based molecules cause pulmonary edema when administered to rats at relatively low doses. However, rats survive normally lethal doses after prior exposure to a lower, nonlethal dose; this phenomenon is known as tolerance. The present study investigated the morphological and functional aspects of acute lung injury (ALI) induced by methylphenylthiourea (MPTU) in the Wistar rat and the pulmonary response involved in prevention of the injury. We identified pulmonary endothelial cells as the main target of acute MPTU injury; they exhibited ultrastructural alterations that can result in increased vascular permeability. In tolerant rats, the lungs showed only transient endothelial changes, at 24-hour post dosing, and mild type II pneumocyte hyperplasia on day 7 post dosing. They exhibited glutathione levels similar to the controls and increased expression of flavin-containing monooxygenase 1 (FMO1), the enzyme responsible for bioactivation of small thioureas in the laboratory rat. Incubation of rat pulmonary microsomal preparations with MPTU inhibited FMO activity, indicating that tolerance is related to irreversible inhibition of FMOs. The rat model of thiourea-induced pulmonary toxicity and tolerance represents an interesting approach to investigate certain aspects of the pathogenesis of ALI and therapeutic approaches to lung diseases, such as acute respiratory distress syndrome.
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PMID:Morphological and Mechanistic Aspects of Thiourea-Induced Acute Lung Injury and Tolerance in the Rat. 3281 62